Piperidinylthioindole derivatives, their methods of preparation and pharmaceutical compositions in which they are present, useful especially as analgesics

ABSTRACT

The present invention relates to the derivatives of the formula ##STR1## and their addition salts, and to their use in therapeutics, especially as drugs having analgesic properties.

The present invention relates, by way of novel products, to thepiperidinylthioindole derivatives of general formula (I) below and theiraddition salts, in particular the pharmaceutically acceptable additionsalts.

The compounds in question have a very valuable pharmacological profileinsofar as they possess analgesic properties. They will therefore beparticularly indicated for the treatment of pain. There may bementioned, for example, their use in the treatment of muscular,articular or neural algia, dental pain, herpes zoster and migraine, andin the treatment of rheumatic complaints and pain of cancerous origin,and also as complementary treatments in infectious and febrile states.

The present invention further relates to the method of preparing saidproducts and to their applications in therapeutics.

These piperidinylthioindole derivatives have general formula (I):##STR2## in which: X₁ and X₂ are independently:

the hydrogen atom;

a halogen atom;

a lower alkyl radical having 1 to 6 carbon atoms;

a trifluoromethyl group; or

a lower O-alkyl radical having 1 to 6 carbon atoms; and can be locatedin the 4-, 5-, 6- or 7-position of the indole ring,

R₁ is:

the hydrogen atom;

a lower alkyl radical having 1 to 6 carbon atoms;

a radical --(CH₂)_(n) -phenyl; or

a radical --(CH₂)_(n) -pyrrole;

in which n is an integer from 0 to 4,

R₂ is:

the hydrogen atom;

a lower alkyl radical having 1 to 6 carbon atoms; or

a phenyl radical which is unsubstituted or substituted by a halogenatom,

R₃ is:

the hydrogen atom;

a lower alkyl radical having 1 to 6 carbon atoms; or

a radical --(CH₂)_(n) -phenyl in which the phenyl is unsubstituted orsubstituted by a halogen atom, n being an integer from 0 to 4, and

p is an integer from 0 to 2.

In the description and the claims, lower alkyl is understood as meaninga linear or branched hydrocarbon chain having from 1 to 6 carbon atoms.A lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexylradical.

Halogen is understood as meaning a chlorine, bromine, iodine or fluorineatom.

The following abbreviations have been used in the description:

Ph: phenyl

phenethyl: 2-phenylethyl

tBu: tert-butyl (1,1-dimethylethyl)

iPr: isopropyl (1-methylethyl)

Me: methyl

Et: ethyl

THF: tetrahydrofuran

Bn: benzyl

In one variant, X₂ is the hydrogen atom.

In one variant, X₁ is the chlorine atom in the 5-position of the indolering.

In another variant, X₁ is the bromine atom in the 5-position of theindole ring.

In another variant, X₁ is the fluorine atom in the 5-position of theindole ring.

In one variant, R₁ is the hydrogen atom.

In another variant, R₁ is a methyl radical.

In another variant, R₁ is a benzyl group.

In one variant, R₂ is a methyl radical.

In another variant, R₂ is the hydrogen atom.

In one variant, R₂ is the hydrogen atom.

In one variant, p is equal to zero.

The particularly preferred compounds of the invention are selected fromthe products of the formulae ##STR3##

According to the invention, the compounds of formula (I) may besynthesized int he following manner:

Reaction of hydrogen sulfide in an alcohol such as, for example,isopropanol, at a temperature below 15° C., with the piperidin-4-ones offormula (II), followed by reduction with sodium or potassium borohydridein an alcohol such as, for example, isopropanol, will give thepiperidine-4-thiols of formula (III) in accordance with the followingscheme: ##STR4## in which formulae (II) and (III), R is a lower alkylradical having 1 to 6 carbon atoms, a benzyl radical, a phenethylradical or a protecting group --COOtBu.

The piperidinones of formula (II) are commercially available with theexception of the one in which R= --COOtBu, which is prepared by reactingditert-butyl dicarbonate with piperidin-4-one or its commerciallyavailable monohydrate by the method described in the followingliterature reference: W. S. SAARI, W. HALCZENKO, J. R. HUFF, J. P. GUAREJr, C. A. HUNT, W. C. RANDALL, V. J. LOTTI, G. G. YARBROUGH; J. Med.Chem. 1984, 27, 1182-5.

The derivatives of formula (III) in which R is the hydrogen atom will beprepared from the derivatives of formula (III) in which R is a methylradical by reaction with ethyl chloroformate in acetone, followed by asecond treatment with ethyl chloroformate in toluene under reflux andthen by a treatment with hydrochloric acid in acetic acid under reflux,in accordance with the following scheme: ##STR5##

This preparative method is described in the following literaturereference:

J. ENGEL, A. BORK, I. NUBERT, H. SCHONENBERGER; Arch. Pharm. (Weinheim)1988, 321, 821-2.

Reaction of the compounds of formula (III), in which R is a lower alkylradical having 1 to 6 carbon atoms, a benzyl radical, a phenethylradical, a protecting group --COOtBu or the hydrogen atom, with ahalogenoketone of formula (IV):

    X--CH.sub.2 --CO--R'                                       Formula (IV)

in which R' is a lower alkyl radical having 1 to 6 carbon atoms or aphenyl radical which is unsubstituted or substituted by a halogen atomand X is a halogen atom, optimally chlorine or bromine, will give thederivatives of formula (V): ##STR6## in which R and R' are as definedabove.

This reaction is carried out in the presence of a sodium, potassium orlithium alcoholate in the corresponding alcohol or in tetrahydrofuran,or else by phase transfer in the presence of sodium or potassiumcarbonate and tetrabutylammonium iodide in toluene at temperaturesbetween 20° and 130° C.

Reaction of the same compounds of formula (III) with a halogenoaldehydewhose aldehyde group is protected by ketalization, of formula (VI):##STR7## in which R" is a lower alkyl having 1 to 6 carbon atoms,optimally methyl or ethyl, or the two radicals R" together form --CH₂--CH₂ --, and X is a halogen atom, optimally chlorine or bromine, willgive the derivatives of formula (VII): ##STR8## in which R and R" are asdefined above.

This reaction is carried out in the same way as for the halogenoketones,for example in the presence of sodium methylate in tetrahydrofuran.

The derivatives of formula (V) or formula (VII) will then be reactedwith phenylhydrazines of formula (VIII): ##STR9## in which X₁, X₂ and R₃are as defined above.

These phenylhydrazines are commercially available or can be prepared bythe conventional methods known to those skilled in the art, for exampleby the diazotization of commercially available anilines of formula (IX):##STR10## in which X₁ and X₂ are as defined above, with sodium nitritein an acid medium, followed by treatment of the diazotized derivativewith stannous chloride to give a phenylhydrazine of formula (X):##STR11## in which X₁ and X₂ are as defined above, after which thisphenylhydrazine is reacted with halogenated derivatives of formula (XI):##STR12## in which R₃ is as defined above and X is a halogen atom, inliquid ammonia and/or tetrahydrofuran, in the presence of sodium amide,at a temperature of -40° C., the reaction mixture being left to returnto room temperature.

The reaction of the derivatives of formula (V) or formula (VII) with thephenylhydrazines of formula (VIII) will be carried out under theconventional conditions of the Fischer synthesis for indole rings,optimally in the presence of gaseous hydrogen chloride in isopropanol at0° C. in order to initiate the reaction, which will subsequently beperformed at room temperature. This reaction gives the derivatives offormula (XII): ##STR13## in which X₁, X₂, R₂ and R₃ are as defined informula (I), R being a lower alkyl radical having 1 to 6 carbon atoms, abenzyl or phenethyl radical or the hydrogen atom.

When the indole formation reaction is performed with compounds in whichR is the group --COOtBu, the compounds of formula (XII) in which R isthe hydrogen atom will be obtained directly.

The compounds of formula (XII) in which R is the hydrogen atom may reactwith halides of formula (XIII): ##STR14## which R₁ is as defined aboveand X is a halogen atom, optimally chlorine, bromine or iodine, to givethe compounds of formula (I) in which p is equal to zero, this reactionbeing carried out in the presence of a tertiary base such astriethylamine or pyridine, or sodium or potassium carbonate, in an inertsolvent such as toluene, at a temperature between 50° and 130° C.

The compounds of formula (I) in which R₃ is the hydrogen atom and p isequal to zero may be alkylated in the 1-position of the indole with thederivatives of formula (XI) by the methods known to those skilled in theart, for example in the presence of a metalating agent such as sodiumamide, sodium, potassium or lithium hydride or a sodium, potassium orlithium alcoholate, in a solvent such as liquid ammonia, tetrahydrofuranor dimethylformamide, at a temperature between -40° C. and 80° C., or inthe presence of sodium hydroxide and a phase transfer agent in toluene.

The resulting compounds of formula (XIV): ##STR15## in which X₁, X₂, R₁,R₂ and R₃ are as defined in formula (I), may be oxidized with anoxidizing agent such as metachloroperbenzoic acid, in a solvent such aschloroform or methylene chloride, at a temperature between 0° and 30°C., to give the compounds of formula (I) in which p is equal to 1 or 2.The amount of oxidizing agent will be chosen so that p=1 or p=2.

The compounds of formula (I) as defined above, and their addition salts,in particular the pharmaceutically acceptable addition salts, possess avery good analgesic activity.

These properties justify their application in therapeutics and theinvention further relates, by way of drugs, to the products as definedby formula (I) above, and their addition salts, in particular thepharmaceutically acceptable addition salts.

The addition salts of the compounds of formula (I) can be obtained byreacting these compounds with a mineral or organic acid by a methodknown per se. Among the acids which can be used for this purpose, theremay be mentioned hydrochloric, hydrobromic, sulfuric, phosphoric,toluene-4-sulfonic, methanesulfonic, cyclohexylsulfamic, oxalic,succinic, formic, fumaric, maleic, citric, aspartic, cinnamic, lactic,glutamic, N-acetylaspartic, N-acetylglutamic, ascorbic, malic, benzoic,nicotinic and acetic acids.

Thus the invention also covers a pharmaceutical composition whichcomprises a pharmaceutically effective amount of at least one compoundof formula (I) as defined above, or one of its pharmaceuticallyacceptable addition salts, which may or may not be incorporated in apharmaceutically acceptable excipient, vehicle or carrier.

These compositions can be administered by the buccal, rectal,parenteral, transdermal, ocular, nasal or auricular route.

These compositions can be solid or liquid and can be in thepharmaceutical forms commonly used in human medicine, such as, forexample, simple or coated tablets, gelatin capsules, granules,suppositories, injectable preparations, transdermal systems, eyelotions, aerosols and sprays, and ear drops. They are prepared by thecustomary methods. The active principle, which consists of apharmaceutically effective amount of at least one compound of formula(I) as defined above, or one of its pharmaceutically acceptable additionsalts, can be incorporated therein with excipients normally employed inthese pharmaceutical compositions, such as talc, gum arabic, lactose,starch, magnesium stearate, polyvidone, cellulose derivatives, cacaobutter, semisynthetic glycerides, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, glycols, various wettingagents, dispersants or emulsifiers, silicone gels, certain polymers orcopolymers, preservatives, flavorings and colors.

The invention also covers a pharmaceutical composition with analgesicactivity affording especially a favorable treatment for pain, whichcomprises a pharmaceutically effective amount of at least one compoundof formula (I) given above, or one of its pharmaceutically acceptableaddition salts, which may or may not be incorporated in apharmaceutically acceptable excipient, vehicle or carrier.

The invention also covers a method of preparing a pharmaceuticalcomposition, which comprises incorporating a pharmaceutically effectiveamount of at least one compound of formula (I) as defined above, or oneof its pharmaceutically acceptable addition salts, into apharmaceutically acceptable excipient, vehicle or carrier. In oneembodiment, a pharmaceutical composition with analgesic activity isprepared which affords especially a favorable treatment for pain.

In one variant, a pharmaceutical composition is formulated as gelatincapsules or tablets containing from 1 mg to 1000 mg of activeingredient, or as injectable preparations containing from 0.1 mg to 500mg of active ingredient. Formulations as suppositories, ointments,creams, gels or aerosol preparations may also be used.

The invention also covers a method of therapeutic treatment for mammals,which comprises administering to this mammal a therapeutically effectiveamount of at least one compound of formula (I) as defined above, or oneof its pharmaceutically acceptable addition salts. In one variant ofthis method of treatment, the compound of formula (I), either by itselfor in association with a pharmaceutically acceptable excipient, isformulated as gelatin capsules or tablets containing from 1 mg to 1000mg of active ingredient for oral administration, or as injectablepreparations containing from 0.1 to 500 mg of active ingredient, or elseas suppositories, ointments, creams, gels or aerosol preparations.

In human and animal therapeutics, the compounds of formula (I) and theirsalts can be administered by themselves or in association with aphysiologically acceptable excipient, in any form, in particular in theform of gelatin capsules or tablets for oral administration or in theform of an injectable solution for parenteral administration. Otherforms of administration, such as suppositories, ointments, creams, gelsor aerosol preparations, can be envisaged.

As will be clearly apparent from the pharmacological tests given at theend of the description, the compounds according to the invention can beadministered in human therapeutics for the afore-mentioned indications,orally in the form of tablets or gelatin capsules containing from 1 mgto 1000 mg of active ingredient, or parenterally in the form ofinjectable preparations containing from 0.1 mg to 500 mg of activeingredient, in one or more daily dosage units for an adult with anaverage weight of 60 to 70 kg.

In animal therapeutics, the daily dose which can be used is between 0.01and 20 mg per kg.

Further characteristics and advantages of the invention will beunderstood more clearly from the following description of some Examples,which in no way imply a limitation but are given by way of illustration.

The method described in the literature (H. BARRERA, R. E. LYLE, J. Org.Chem. (1962) 27, 641-2) is used to prepare 1-methylpiperidine-4-thiol(formula III in which R=methyl) and the following thiols:

EXAMPLE 1 1-(Phenylmethyl)piperidine-4 thiol

    Formula (III): R=CH.sub.2 Ph

Oil.

¹ H NMR (CDCl₃): 7.15-7.4 (m, 5H); 3.48 (s, CH₂ benz); 2.65-2.9 (m,2CH+SCH); 1.9-2.15 (m, 4CH); 1.55-1.75 (m, 2CH); 1.5 (d, SH, J=7 Hz).

EXAMPLE 2 1-(2-Phenylethyl)piperidine-4-thiol

    Formula (III): R=CH.sub.2 CH.sub.2 Ph

Oil.

¹ H NMR (CDCl₃): 7.15-7.35 (m, 5H); 2.9-3.05 (m, 2CH); 2.65-2.9 (m, CH₂+SCH); 2.5-2.65 (m, CH₂); 1.95-2.25 (m, 4CH); 1.6-1.85 (m, 2CH); 1.54(d, SH, J=7.1

EXAMPLE 3 1,1-Dimethylethyl 4-mercaptopiperidine-1-carboxylate

    Formula (III): R=CO.sub.2 tBu

Oil.

¹ H NMR (CDCl₃): 155.0 (Cq); 79.7 (Cq); 43.6 (CHS); 36.5 (CH₂); 36.1(CH₂); 28.5 (CH₃).

EXAMPLE 4 1-(1 Methylethyl)piperidine 4-thiol

    Formula (III): R=iPr

Oil.

¹ H NMR (CDCl₃): 2.6-2.9 (m, 4H); 2.1-2.3 (m, 2CH); 1.95-2.1 (m, 2CH);1.51 (d, SH, J=7.6 Hz); 1.5-1.75 (m, 2CH); 1.02 (d, 2CH₃, J=6.5 Hz).

EXAMPLE 5 1-Methyl-4-[(2-oxopropyl)thio]piperidine

    Formula (V): R=Me, R'=Me

Sodium methylate (5.9 g) is added in portions to a solution of1-methylpiperidine-4-thiol (14 g) in anhydrous tetrahydrofuran (100 ml)at room temperature. After 2 hours at this temperature, chloroacetone(8.8 ml) is added dropwise. After 24 hours, the precipitate is filteredoff and the filtrate is concentrated and chromatographed on silica gel(eluent: ethyl acetate, then ethanol) to give1-methyl-4-[(2-oxopropyl)thio]-piperidine (11.5 g) in the form of anoil.

¹ H NMR (CDCl₃): 3.28 (s, CH₂ S); 2.75-2.90 (m, (2H); 2.5-2.7 (m, CHS);2.30 (s, CH₃ N); 2.25 (s, CH₃); 1.85-2.15 (m, 4H); 1.5-1.75 (m, 2H).

The following compounds (Examples 6 and 7) were prepared by using thesame method with the appropriate chloroketones and piperidine-4-thiols:

EXAMPLE 6 4-[(2-Oxopropyl)thio]piperidine

    Formula (V): R=H, R'=Me

Yellow solid: m.p.=136° C.

Hydrochloride: m.p.=118° C.

¹ H NMR (CDCl₃): 3.2 (s, CH₂ S); 2.95-3.1 (m, 2H); 2.45-2.75 (m, 3H+NH);2.23 (s, CH₃); 1.75-1.95 (m, 2H); 1.25-1.5 (m, 2H).

EXAMPLE 7 4-[[2 (4 Chlorophenyl)-2 oxoethyl]thio]-piperidine

    Formula (V): R=H, R'=4-Cl-Ph

Orange solid: m.p.=202° C.

¹ H NMR (CDCl₃): 7.9 (d, 2CH, J=8.5 Hz); 7.43 (d, 2CH, J 8.5 Hz); 3.75(s, SCH₂); 2.95-3.25 (m, 2H+HN); 2.7-2.9 (m, SCH); 2.5-2.7 (m, 2CH);1.85-2.05 (m, 2CH); 1.35-1.6 (m, 2CH).

EXAMPLE 8 4-[(2-Oxopropyl)thio]-I (phenylmethyl)-piperidine

    Formula (V): R=CH.sub.2 Ph, R'=Me

A suspension of 1-(phenylmethyl)piperidine-4-thiol (70 g, prepared inExample 1), chloroacetone (26.9 ml), sodium carbonate (71.6 g) andtetrabutylammonium iodide (31.2 g) in toluene (350 ml) is stirred atroom temperature for 4 hours. The insoluble material is filtered off andwashed with toluene. After concentration, the filtrate is taken up indichloromethane and washed with dilute sodium hydroxide and then with asaturated aqueous solution of sodium chloride. After drying over sodiumsulfate, the solution is concentrated to give4-[(2-oxopropyl)thio]-1-(phenylmethyl) piperidine (82.2 g) in the formof an oil, which is sufficiently pure to be used in the next step.

¹ H NMR (CDCl₃): 7.15-7.35 (m, 5H); 3.5 (s, CH₂ benz); 3.2 (s, SCH₂);2.75-2.95 (m, 2H); 2.55-2.75 (m, SCH); 2.28 (s, CH₃); 1.85-2.15 (m, 4H);1.5-1.75 (m, 2CH).

The following compounds (Examples 9 and 10) were prepared by using thesame method of synthesis with the appropriate piperidine-4-thiols:

EXAMPLE 9 4-[(2-Oxopropyl)thio]-1-(2-phenylethyl)piperidine

    Formula (V): R=CH.sub.2 CH.sub.2 Ph, R'=Me

Oil.

¹ H NMR (CDCl₃): 7.1-7.35 (m, 5H); 3.27 (s, SCH₂); 2.85-3.05 (m, 2H);2.75-2.85 (m, 2H); 2.5-2.75 (m, 3H); 2.29 (s, CH₃); 1.9-2.2 (m, 4H);1.5-1.8 (m, 2H).

EXAMPLE 10 1,1-Dimethylethyl 4-[(2oxopropyl)thio]-piperidine-1-carboxylate

    Formula (V): R=CO.sub.2 tBu, R'=Me

Oil.

¹ H NMR (CDCl₃): 3.9-4.05 (m, 2CH); 3.26 (s, SCH₂); 2.7-3 (m, 2CH+SCH);2.32 (s, CH₃); 1.85-2 (m, 2CH); 1.35-1.6 (m, 2CH); 1.45 (s, 3CH₃).

EXAMPLE 11 4-[(2,2-Diethoxyethyl)thio]-1-methylpiperidine

    Formula (VII): R=Me, R"=Et

Sodium methylate (18.1 g) is added in portions to a solution of1-methylpiperidine-4-thiol (22 g) in anhydrous tetrahydrofuran (200 ml).After one hour, the diethyl acetal of bromoacetaldehyde (30.3 ml) isadded. After 4 hours at room temperature, the solution is heated for 2hours at 40° C. The insoluble material is filtered off and rinsed withTHF. The filtrate is concentrated and then distilled under reducedpressure to give 4-[(2,2-diethoxyethyl)thio]-1-methylpiperidine (36 g;b.p.=104°-108° C. under 0.05 atm) in the form of an oil.

¹ H NMR (CDCl₃): 4.6 (t, 1H, J=5.6 Hz); 3.45-3.8 (m, 2CH₂ O); 2.65-2.9(m, 3CH); 2.72 (d, SCH₂, J=5.6 Hz); 2.26 (s, NCH₃); 1.9-2.1 (m, 4CH);1.5-1.75 (m, 2CH); 1.22 (t, 2CH₃, J=7 Hz).

Compounds 12 and 13 are also prepared by using the same method:

EXAMPLE 12 4-[(2,2-Diethoxyethyl)thio]-1-(phenylmethyl)piperidine

    Formula (VII): R=CH.sub.2 Ph, R"=Et

Oil

¹ H NMR (CDCl₃): 7.2-7.4 (m, 5H); 4.6 (t, 1H, J=5.6 Hz); 3.46 (s, CH₂benz); 3.5-3.8 (m, 2CH₂ O); 2.65-2.95 (m, 4H); 2.75 (d, SCH₂, J=5.6 Hz);1.85-2.15 (m, 4H); 1.5-1.8 (m, 2H); 1.22 (t, 2CH₃, J=7 Hz).

EXAMPLE 13 4-[(2,2-Diethoxyethyl)thio]-1-(1 methylethyl)piperidine

    Formula (VII): R=iPr, R"=Et

Oil.

¹ H NMR (CDCl₃): 4.60 (t, 1H, J=5.6 Hz); 3.45-3.75 (m, 2CH₂ O); 2.6-2.9(m, 4H); 2.73 (d, CH₂ S, J=5.6 Hz); 2.1-2.25 (m, 2CH); 1.9-2.05 (m,2CH); 1.5-1.7 (m, 2CH); 1.22 (t, 2CH₃, J=7 Hz); 1.02 (d, 2CH₃, J=6.6Hz).

EXAMPLE 142,5-Dimethyl-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indolehydrochloride ##STR16##

Paratolylhydrazine hydrochloride (20 g) is added to a solution of4-[(2-oxopropyl)thio]-1-(phenylmethyl)piperidine (33.2 g), prepared inExample 8, in isopropanol (150 ml) under nitrogen. After 30 minutes, thesolution is cooled to 0° C. and saturated with gaseous hydrogenchloride. After 4 hours at room temperature, the precipitate formed isfiltered off, washed with water and then taken up in hot ethanol. Aftercooling, the white crystals of 2,5-dimethyl-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indole hydrochloride (28.3 g) are filtered off.

C₂₂ H₂₆ N₂ S.HCl.

M.p.=258° C.

The following compounds (Examples 15 to 32) were prepared by using thesame method of synthesis with the appropriate hydrazines and ketones:

EXAMPLE 15 5-Chloro-2-methyl-3-(piperidin-4 ylthio)-1H-indole ##STR17##

Off-white solid.

C₁₄ H₁₇ ClN₂ S.

M.p.=198°-199° C.

EXAMPLE 16 5-Fluoro 2-methyl-3-(piperidin-4-ylthio)-1H-indole ##STR18##

White solid.

C₁₄ H₁₇ FN₂ S.

M.p.=201° C. (purified by chromatography on silica gel with thefollowing eluent: CHCl₃ /MeOH/NH₄ OH : 80/20/1).

EXAMPLE 17 5-Methoxy-2-methyl-3-(piperidin-4 ylthio)-1H-indole ##STR19##

Pale yellow solid.

C₁₅ H₂₀ N₂ OS.

M.p.=217°-218° C. (recrystallized from xylene).

EXAMPLE 18 2-Methyl-3-(piperidin-4-ylthio)-5-(trifluoromethyl)-1H-indole hydrochloride ##STR20##

White solid.

C₁₅ H₁₇ F₃ N₂ S.HCl.

M.p.=298°-301° C. (recrystallized from water).

EXAMPLE 19 5,7-Dichloro-2-methyl-3-(piperidin-4-yl-thio)-1H-indolehydrochloride ##STR21##

Beige solid.

C₁₄ H₁₆ Cl₂ N₂ S.HCl.

M.p.>275° C.

EXAMPLE 20 b 4,6-Dichloro-2-methyl-3-(piperidin-4-yl-thio)-1H-indolehydrochloride ##STR22##

Beige solid.

C₁₄ H₁₆ Cl₂ N₂ S.HCl.

M.p.>275° C.

EXAMPLE 21 5-Chloro-2-(4-chlorophenyl)-3-(piperidin-4-ylthio)-1H indole##STR23##

Pale yellow solid.

C₁₉ H₁₈ Cl₂ N₂ S.

M.p.=230°-231° C. (recrystallized from xylene).

EXAMPLE 22 5--Chloro 1-[(4 chlorophenyl)methyl]-2-methyl-3-(piperidin-4ylthio) -1H-indole ##STR24##

White solid.

C₂₁ H₂₂ Cl₂ N₂ S.

M.p.=122° C.

EXAMPLE 23 5--Chloro-2-methyl-3-[(1-methylpiperidin-4-yl)thio]-1H-indole##STR25##

Beige solid

C₁₅ H₁₉ ClN₂ S.

M.p. 154°-157° C. (recrystallized from cyclohexane).

EXAMPLE 24 5-Fluoro-2-methyl-3-[(1-methylpiperidin-4-yl) thio]-1H-indole##STR26##

Pale yellow solid.

C₁₅ H₁₉ FN₂ S.

M.p.=158°-159° C. (recrystallized from cyclohexane).

EXAMPLE 255-Bromo-2-methyl-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indolehydrochloride ##STR27##

White solid.

C₂₁ H₂₃ BrN₂ S.HCl.

M.p.=266°-267° C.

EXAMPLE 26 5 Chloro-2,7-dimethyl-3-[[1-(phenylmethyl)piperidin-4yl]thio]-1H-indole hydrochloride ##STR28##

White solid.

C₂₂ H₂₅ ClN₂ S.HCl.

M.p. 245°-246° C. (recrystallized from acetonitrile).

EXAMPLE 27 7-Chloro-2-methyl 3-[[1-(phenylmethyl)piperidin-4yl]thio]-1H-indole ##STR29##

White solid.

C₂₁ H₂₃ ClN₂ S.

M.p.=133°-134° C. (recrystallized from ethanol).

EXAMPLE 284,7-Dichloro-2-methyl-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indolehydrochloride ##STR30##

Beige solid.

C₂₁ H₂₂ Cl₂ N₂ S.HCl.

M.p.=143°-144° C.

EXAMPLE 29 5-Chloro-1,2-dimethyl-3-[[1-(phenylmethyl)piperidin-4yl]thio]-1H-indole hydrochloride ##STR31##

White solid.

C₂₂ H₂₅ ClN₂ S.HCl.

M.p.=231°-233° C.

EXAMPLE 305-Chloro-2-methyl-3-[[1-(2-phenylethyl)piperidin-4-yl]thio]-1H-indole##STR32##

Pale yellow solid.

C₂₂ H₂₅ ClN₂ S.

M.p.=190°-192° C.

EXAMPLE 315-Bromo-2-methyl-3-[[1-(2-phenylethyl)piperidin-4-yl]thio]-1H-indole##STR33##

White solid.

C₂₂ H₂₅ BrN₂ S.

M.p. 188°-189° C. (recrystallized from acetonitrile).

EXAMPLE 32 5-Chloro-1,2-dimethyl-3-[[1-(2-phenylethyl)piperidin-4-yl]thio]-1H-indole ##STR34##

White solid.

C₂₃ H₂₇ ClN₂ S.

M.p.=136°-137° C. (recrystallized from acetonitrile).

EXAMPLE 33 5--Chloro-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indolehydrochloride ##STR35##

4-Chlorophenylhydrazine hydrochloride (1 g) and4-[(2,2-diethoxyethyl)thio]-1-(phenylmethyl)piperidine (prepared inExample 12) in isopropanol (20 ml) are stirred at room temperature undernitrogen until a solution is formed. After cooling to 0° C., thesolution is saturated with gaseous hydrogen chloride. After 4 hours, theprecipitate is filtered off, taken up in sodium hydroxide and extractedwith ether and then with ethyl acetate. The combined organic phases aredried over sodium sulfate and concentrated. The residual oil is taken upin a solution of hydrogen chloride in ether to give5-chloro-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indolehydrochloride (1.4 g).

White solid.

C₂₀ H₂₁ ClN₂ S.HCl.0.5H₂ O.

M.p.=158°-160° C.

The following compounds (Examples 34 to 43) were prepared by using thesame method of synthesis with the appropriate hydrazines and acetals:

EXAMPLE 34 5 Bromo-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indole##STR36##

White solid.

C₂₀ H₂₁ BrN₂ S.

M.p. 134°-135° C. (recrystallized from cyclohexane).

EXAMPLE 35 3-[[1-(Phenylmethyl)piperidin 4-yl]thio]-5-(trifluoromethyl)-1H indole ##STR37##

White solid.

C₂₁ H₂₁ F₃ N₂ S.

M.p. 154°-155° C. (recrystallized from cyclohexane).

EXAMPLE 36 1-Phenyl-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indoleoxalate ##STR38##

Beige solid.

C₂₆ H₂₆ N₂ S.C₂ H₂ O₄.

M.p.=193°-194° C. (recrystallized from ether).

EXAMPLE 37 5-Chloro-3-[(1-methylpiperidin-4-yl)thio]-1H-indole ##STR39##

Off-white solid.

C₁₄ H₁₇ ClN₂ S.

M.p. 136°-137° C. (recrystallized from cyclohexane).

EXAMPLE 38 5-Methoxy-3-[(1-methylpiperidin 4-yl)thio]-1H-indole##STR40##

Beige solid.

C₁₅ H₂₀ N₂ OS.

M.p.=153° C. (recrystallized from isopropanol).

EXAMPLE 39 3-[(1-Methylpiperidin-4 yl)thio]-1H-indole ##STR41##

Pale yellow solid.

M.p.=143°-144° C. (recrystallized from cyclohexane).

EXAMPLE 40 5-(1-Methylethyl)-3-[(1-methylpiperidin-4-yl) thio]-1H-indole##STR42##

Off-white solid.

M.p.=110° C.

EXAMPLE 41 5-Bromo-3-[(1-methylpiperidin-4-yl)thio]1H-indole ##STR43##

Light beige solid.

M.p.=135°-136° C. (recrystallized from cyclohexane).

EXAMPLE 42 5-Bromo-3-[[1-(1-methylethyl)piperidin-4-yl]thio]-1H-indole##STR44##

Beige solid.

C₁₆ H₂₁ BrN₂ S.

M.p. 116°-118° C. (recrystallized from acetonitrile).

EXAMPLE 43 5-Chloro-3-[[1-(1-methylethyl)piperidin-4-yl]thio]-1H-indole##STR45##

Light beige solid.

C₁₆ H₂₁ ClN₂ SD.

M.p.=123° C. (recrystallized from cyclohexane).

EXAMPLE 44 5-Bromo-2-methyl-3 (piperidin-4 ylthio)-1H-indole ##STR46##

4-Bromophenylhydrazine hydrochloride (11.5 g) is solubilized in asolution of 1,1-dimethylethyl4-[(2-oxopropyl)thio]piperidine-1-carboxylate (prepared in Example 10)in isopropanol (100 ml) under nitrogen. The solution is cooled to 0° C.and saturated with gaseous hydrogen chloride. After 4 hours at roomtemperature, the precipitate is filtered off, taken up in sodiumhydroxide and extracted with ether and then with methylene chloride. Theorganic phases are combined, dried over sodium sulfate and concentrated.The solid obtained is taken up in the minimum amount of ether andrecrystallized from xylene to give5-bromo-2-methyl-3-(piperidin-4-ylthio) -1H-indole (9.5 g).

Pale yellow solid.

C₁₄ H₁₇ BrN₂ S.

M.p.=207°-208° C.

EXAMPLE 45 5-Chloro-2-methyl-3-[[1-[2-(1H-pyrrol-1-yl)ethyl]piperidin-4-yl]thio]-1H indole ##STR47##

A toluene solution (100 ml) of 5-chloro-2-methyl-3-(piperidin-4-ylthio)-1H-indole (1.09 g, prepared in Example 15), sodium carbonate (0.78 g)and 1-(2-iodoethyl) -1H-pyrrole (0.92 g, prepared according to GALEAZZI,E.; GUZMAN, A.; PINEDO, A.; SALDANA, A.; TORRE, D.; MUCHOWSKI, J. M.,Can. J. Chem. (1983) 61, 454-60) is refluxed for 15 hours. The reactionmixture is taken up in a water/dichloromethane mixture. The organicphase is dried over magnesium sulfate and concentrated. The residue ischromatographed on silica gel (eluent: CH₂ Cl₂ /MeOH : 90/10) to give5-chloro-2-methyl-3-[[1-[2-(1H-pyrrol-1-yl)ethyl]piperidin-4-yl]thio]-1H-indole (0.9 g).

Off-white solid.

C₂₀ H₂₄ ClN₃ S.

M.p.=169°-171° C.

EXAMPLE 46 3-[[1-(Phenylmethyl)piperidin4-yl]thio]-1,2,5-trimethyl-1H-indole ##STR48##

An aqueous solution (200 ml) of 2,5-dimethyl-3-[[1-(phenylmethyl)piperidin-4-yl]thio]-1H-indole hydrochloride (prepared in Example 14) isrendered basic to pH 9 with sodium hydroxide. After extraction withether, the organic phase is dried over sodium sulfate and concentrated.The indole crystallizes (10.4 g) after the addition of heptane.

A solution of this indole (10 g) in anhydrous tetrahydrofuran (50 ml) isadded dropwise to a solution of sodium amide (1.3 g) in liquid ammonia(20 ml) at -40° C. After 10 minutes, methyl iodide (2 ml) intetrahydrofuran (50 ml) is added.

After 2 hours at room temperature, 10 ml of water are added. Afterconcentration, the mixture is taken up in water and extracted with ethylacetate. The organic phase is dried over sodium sulfate andconcentrated.3-[[1-(Phenylmethyl)piperidin-4-yl]thio]-1,2,5-trimethyl-1H-indole (8.3g) is obtained after recrystallization from ethanol.

White solid.

C₂₃ H₂₈ N₂ S.

M.p.=134°-135° C.

EXAMPLE 47 5--Chloro-2-methyl-3-(piperidin-4-ylsulfinyl)-1H-indole##STR49##

Metachloroperbenzoic acid (2.79 g) is added in portions to a solution of5-chloro-2-methyl-3-(piperidin-4-ylthio) -1H-indole (3 g, prepared inExample 15) in dichloromethane (25 ml) at -40° C. After 4 hours at roomtemperature, the insoluble material is filtered off. The filtrate iswashed with sodium hydroxide and then with water. The aqueous phases areextracted with ether and then with ethyl acetate. The organic phases arecombined, dried over magnesium sulfate and concentrated. The oilyresidue obtained is chromatographed on silica gel (eluent: CH₂ Cl₂/MeOH/NH₄ OH : 90/10/1) to give5-chloro-2-methyl-3-(piperidin-4-yl-sulfinyl)-1H-indole in the form ofan oil, which crystallizes on the addition of ether (0.4 g).

Beige solid.

C₁₄ H₁₇ ClN₂ OS.H₂ O.

M.p.=140°-145° C.

PHARMACOLOGY

The analgesic activity of the products of the Examples was evaluated bythe method involving the stretching movements caused byphenylbenzoquinone in mice, described by Siegmund et al. (1957).

Method

The intraperitoneal injection of phenylbenzoquinone causes twisting andstretching movements in mice. Analgesics prevent or reduce thissyndrome, which can be considered as the exteriorization of diffuseabdominal pain.

A 0.02% solution of phenylbenzoquinone in water is administered in avolume of 1 ml/100 g.

The products of the Examples are administered orally one hour before theinjection of phenylbenzoquinone.

The stretching and twisting movements are counted for each mouse over anobservation period of 5 minutes.

Expression of the Results

The results are expressed in the form of the ID₅₀, i.e. the dose whichmakes it possible to obtain a 50% reduction in the number of painreactions compared with the control animals.

Results

The results are presented in the Table below.

    ______________________________________                                                     50% inhibitory dose                                              Product of   mg/kg p.o.                                                       ______________________________________                                        Example 15   0.8                                                              Example 16   5.9                                                              Example 23   11                                                               Example 33   9.7                                                              Example 37   4                                                                Example 44   0.7                                                              ______________________________________                                    

TOXICOLOGY

The preliminary toxicology studies performed show that the products ofthe Examples do not induce any deleterious effect in rats after the oralabsorption of doses which can vary form 30 to 300 mg/kg.

What is claimed is:
 1. A piperidinylthioindole compound of formula (I):##STR50## in which: X₁ and X₂ are independently:a hydrogen atom; ahalogen atom; a lower alkyl radical having 1 to 6 carbon atoms; atrifluoromethyl group; or a lower O-alkyl radical having 1 to 6 carbonatoms; and can he located in the 4-, 5-, 6- or 7-position of the indolering, R₁ is:a hydrogen atom; a lower alkyl radical having 1 to 6 carbonatoms; a radical --(CH₂)_(n) -phenyl; or a radical --(CH₂)_(n)-pyrrole;in which n is an integer from 0 to 4, R₂ is:a hydrogen atom; alower alkyl radical having 1 to 6 carbon atoms; or a phenyl radicalwhich is unsubstituted or substituted by a halogen atom, R₃ is:ahydrogen atom; a lower alkyl radical having 1 to 6 carbon atoms; or aradical --(CH₂)_(n) -phenyl in which the phenyl is unsubstituted orsubstituted by a halogen atom, n being an integer from 0 to 4, and p isan integer from0 to 2, or a pharmaceutically acceptable addition saltthereof.
 2. A compound according to claim 1 wherein X₂ is a hydrogenatom and X₁ is a halogen atom and is located in the 5-position of theindole.
 3. A compound according to claim 1 wherein R₁ is a hydrogenatom, a methyl radical or a benzyl group.
 4. A compound according toclaim 1 wherein R₂ is a hydrogen atom or a methyl radical.
 5. A compoundaccording to claim 1 wherein R₃ is a hydrogen atom.
 6. A compoundaccording to claim 1 wherein p is equal to zero.
 7. A compound accordingto claim 1 which is selected from the derivatives of the formulae:##STR51##
 8. A pharmaceutical composition with analgesic activity, whichcontains a pharmaceutically effective amount of a compound of formula(I) as defined in claim 1, or a pharmaceutically acceptable additionsalt thereof, incorporated in a pharmaceutically acceptable excipient,vehicle or carrier.
 9. A pharmaceutical composition according to claim8, which is formulated as a gelatin capsule or a tablet containing form1 mg to 1000 mg of active ingredient.
 10. A pharmaceutical compositionaccording to claim 8, which is formulated as an injectable preparationscontaining from 0.1 to 500 mg of active ingredient.
 11. A method oftherapeutic treatment of mammals for pain, which comprises administeringto this mammal a therapeutically effective amount of a compound offormula (I) as defined in claim 1 or one of its pharmaceuticallyacceptable addition salt.